From initiation to promotion and to the development of an invasive phenotype, a series of molecular changes contribute to those aberrations and puts the entire airway epithelium of smokers at a greater risk for lung cancer. Our central hypothesis is that a subset of specific molecular aberrations discovered in pre-invasive lesions and from the airway epithelium of high-risk individuals is directly involved in the development of lung cancer, and that derivation of a signature composed of these functionally significant alterations in at-risk individuals will represent a powerful biomarker for risk as well as an intermediate endpoint biomarker of response to chemoprevention therapy. To test this hypothesis, we propose to use two separate approaches to interrogate the field of carcinogenesis. In aim 1 we will study the biological relevance of candidate biomarkers derived from the analysis of preinvasive lesions obtained in the current cycle of funding. In aim 2 we will refine a gene expression signature derived from the bronchial epithelial cells from the large airways by stratifying the population further and integrating data from state of the art genomic and proteomic analyses in specimens obtained from the same individuals. In aim 3, we will test the candidates from aims 1 and 2 in preinvasive lesions from bronchial epithelial cells for risk assessment and as intermediate endpoint biomarkers of chemoprevention therapy. The studies proposed are highly novel in their focus on functionally relevant biomarkers, the testing for biomarkers that track with the disease risk, and the application of multiple cutting edge technologies. These studies will further our understanding of the functional role of our candidate biomarkers in lung cancer development, refine a molecular signature of risk in large airway epithelial cells and test those in high-risk cohorts for new molecular diagnostic and intermediate endpoint biomarker of response to chemoprevention.